This grant application proposes laboratory research projects to continue a productive line of research into the behavioral, neurochemical, and anatomic characterization of new antipsychotic drugs. The new generation of antipsychotic drugs has swept clinical markets around the world because of the full clinical actions of the compounds and their reduced motor side effect profiles. This project aims to compare the two most widely used antipsychotics (risperidone and olanzapine), and contrast them with a traditional drug (haloperidol) in a chronic animal treatment model with informative mouse behavior, neurochemical and anatomic assays. We will test effects of the two new antipsychotic drugs and haloperidol on two mouse behaviors when applied acutely and after 1,2,3, and 4 months of antipsychotic treatment: (1) PCP-disrupted prepulse inhibition (PPI) (purportedly modeling for attentional dysfunction in schizophrenia) and (2) PCP-disruption of social learning (purportedly modeling for learning dysfunction). Concurrently, we will analyze neurochemical and anatomic markers of neurotransmitter pathways in CNS, especially in those regions where clinical schizophrenia studies have localized attentional and cognitive dysfunction. The behavioral, neurochemical, and anatomic changes will be correlated over treatment time in each drug group and contrasted between drugs. These studies are a continuation of a productive approach aimed at studying antipsychotic drug actions using behavior (oral dyskinesias) to mark the drug action and regional neurochemical correlates to establish the putative mechanism (see Progress Report). We can expect that new antipsychotic drugs will have not only actions on positive symptoms but also display low motor side effects (acute and chronic) and ameliorate the short term memory and the attentional dysfunction of schizophrenia. Animal measures of these "new" actions could expedite drug development in this "new" broader and more complex direction. Concentration on mouse behaviors, neurochemistry and behavior will advance studies aimed at kinetic applications.